The invention concerns the preparation of diisopinocampheylchloroborane. The invention also relates to the use of a crude diisopinocampheylchloroborane product in the reduction of prochiral ketones.
Diisopinocampheylchloroborane is a well known chiral reducing agent, and several methods for its preparation have been reported. In one early reference (Brown, H. C. and Jadhav, P. K., J. Am. Chem. Soc., 1983, 105, 2092-2093), diisopinocampheylchloroborane was prepared by reacting monochloroborane etherate with .alpha.-pinene in diethyl ether. The monochloroborane etherate was in turn prepared from lithium borohydride and boron trichloride (Brown, H. C. and Ravindran N., J. Am. Chem. Soc., 1972, 94, 2112-3). U.S. Pat. No. 5,043,479 reported that the above process produced a product mixture which was unsatisfactory for achieving asymmetric reduction of ketones in high enantiomeric excess.
U.S. Pat. No. 5,043,479 further reported a novel method for the preparation of diisopinocampheylchloroborane. In this process, the intermediate diisopinocampheylborane must first be prepared and isolated by crystallization. This intermediate is highly sensitive to both oxygen and water, thus complicating its isolation. The enantiomeric purity of diisopinocampheylchloroborane was increased to &gt;99% after crystallization, starting from .alpha.-pinene of an optical purity of approximately 90%. This upgrading of the enantiomeric purity of diisopinocampheylchloroborane via crystallization was deemed critical for obtaining maximum enantioselectivity in the reduction of ketones to alcohols. See Brown, H. C. et al, J. Org. Chem., 1987, 52, 5406 and references therein; Brown, H. C. et al, J. Org. Chem., 1986, 51, 3394; Srebnik, M. et al, J. Org. Chem., 1988, 53, 2916; and Brown, H. C. et al, J. Am. Chem. Soc., 1988, 1539.
In U.S. Pat. No. 5,292,946 it was reported that diisopinocampheylchloroborane prepared in-situ, without isolation or discrete purification of either the final product or the intermediate diisopinocampheylborane, performs in an equal manner to the isolated reagent. The processes in U.S. Pat. 5,043,479 and 5,292,946 both require the use of the corrosive reagent hydrogen chloride, and are therefore less than ideal for industrial application.
In yet another process (King, A. O. et al, J. Org. Chem., 1993, 58, 3731-5), diisopinocampheylchloroborane was prepared from monochloroborane-dimethylsulfide complex and .alpha.-pinene. The boron source in this process contains the stench compound dimethylsulfide, making it an undesirable reagent to use in large amounts.
The prior reported processes all require the use of either borane or monochloroborane, both of which are expensive reagents and both are very sensitive to oxygen and moisture. Therefore, there exists the need for an economical, convenient and efficient method for the preparation of a diisopinocampheylchloroborane product suitable for the reduction of prochiral ketone to give hydroxy compounds with high optical purity.